Calculations of O2 and CO2 transfer in lung models of both series and parallel ventilation-perfusion (VA/Q) inequality have been performed by several investigators. In some cases, O2 uptake was found to be depressed more than CO2 output but in other examples CO2 elimination was interfered with to a greater extent. To understand the fundamental basis of differential susceptibility of various gases to VA/Q inequality, an algebraic analysis of inert gas exchange in two-compartment models of both series and parallel inequality is presented. For both types of inequality, the result is remarkably simple, in that the gas most affected is one whose partition coefficient is the geometric mean of the ventilation-to-perfusion ratios of the two compartments. Transfer of O2 and CO2 in these models was predicted well by the inert gas results not only qualitatively but even quantitatively. Similarly good quantitative predictions were obtained in more complicated multicompartment VA/Q distributions. The results therefore explain and reconcile the findings of various reported studies and in particular account for the observation that CO2 transfer is compromised in many examples of series inequality.